CN101037427A - Preparation method of tested and reference mycophenolate mofetil - Google Patents
Preparation method of tested and reference mycophenolate mofetil Download PDFInfo
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- CN101037427A CN101037427A CN 200710086597 CN200710086597A CN101037427A CN 101037427 A CN101037427 A CN 101037427A CN 200710086597 CN200710086597 CN 200710086597 CN 200710086597 A CN200710086597 A CN 200710086597A CN 101037427 A CN101037427 A CN 101037427A
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Abstract
The invention is provided with a preparing method for mycophenolate mofetil which does not use solvent during esterification, but esterifying the mycpphenolic acid and morpholinoethanol in 120-150 DEG C in the existence of antioxidant vitamin C so as to solve color bum difficulty, reduce the decoloring agent use dosage in the subsequent disposal, reduce the production cost, improve the product quality, while maintaining the synthesis efficiency. The inventive product is white solid powder. The invention is a craft suitable for commercial process and obtains improved product quality with a purity more than 99.7% and has a low cost.
Description
Technical field
The present invention relates to the preparation of compound, particularly the preparation method of mycophenolate mofetile.
Background technology
{ [E-6-(1 for the neotype immunosuppressant mycophenolate mofetile, 3-dihydro-4-hydroxyl-6-methoxyl group-7-methyl-3-oxo-5-isobenzofuran-base)-4-methyl-4-olefin(e) acid-2-morpholino ethyl ester], (Mycophenolate Mofetil, MMF, U.S. Pat P4753935) } be Mycophenolic Acid (Mycophenolic acid, MPA) 2-ethyl morpholine ester derivative, its structure is suc as formula shown in (I):
In the formula (I), R
1=H, R
2=2-(4-morpholinyl) ethyl.Mycophenolate mofetile forms the meta-bolites MPA with immunosuppressive activity after taking off ester in vivo, and the latter is by suppressing the synthetic of guanine, and the propagation of selective exclusion T and bone-marrow-derived lymphocyte all has significant curative effect to transplant rejection and autoimmune disorder.Be applied to organ transplantation and autoimmune disorder clinically, and few side effects, good prospects for application shown.
Existing patent documentation shows that the synthetic method of mycophenolate mofetile has two lines: a kind of is indirect esterification process, promptly examine the phenol acyl chlorides with Mycophenolic Acid and acyl chloride reaction production wheat after, again with hydroxyethyl morpholine esterification generation mycophenolate.Another kind is to be the technology of representative with U.S. Pat P5247083 patent, promptly Mycophenolic Acid toluene, dimethylbenzene or other boiling points in 120-150 ℃ inert organic solvents with hydroxyethyl morpholine direct esterification production under reflux state.Article two, all there is defective in operational path, adopts the former to cause relative substance increase in the product, and target product content is on the low side.The latter causes product purple to occur, needs to use the activated carbon more than 40% of Mycophenolic Acid charging capacity could eliminate color.
In addition, Canadian Patent CA2493508 discloses a kind of new synthetic process of mycophenolate mofetile, this technology is not used organic solvents such as toluene, benzene in esterification reaction process, and the oxide compound of interpolation zinc powder, zinc salt and zinc etc., adopt this technology, synthetic weight total recovery has only about 92%, and production cost is higher.CN1733749A adopts the synthetic mycophenolate mofetil (being mycophenolate mofetile) of molecular distillation technique, under high vacuum, make mycophenolic acid (being Mycophenolic Acid) and 2-morpholino ethanol (being morpholine ethanol) be gasificated into molecule, the synthetic mycophenolate mofetil of rapid reaction between the molecule, the advantage of this method is short a, good product quality of reaction times, shortcoming is that the equipment one-time investment is too big, and energy consumption is higher.
Summary of the invention
In order to solve the problems of the technologies described above, the invention provides a kind of quality product height and the preparation method of the low mycophenolate mofetile of production cost, its technical scheme is as follows:
A kind of preparation method of mycophenolate mofetile may further comprise the steps:
(1) Mycophenolic Acid and morpholine ethanol are mixed by weight 1: 3～7, add vitamins C simultaneously, carry out esterification at 120 ℃～150 ℃ as antioxidant;
(2) cool to room temperature, with butylacetate or ethyl acetate or the dissolving of its mixture;
(3) with the sodium hydrogen carbonate solution washing, collect organic phase;
(4) organic phase is decoloured with discoloring agent;
(5) concentrating under reduced pressure, decrease temperature crystalline;
(6) isolation of crystalline is drying to obtain the mycophenolate mofetile product.
Ascorbic consumption is preferably Mycophenolic Acid weight 1%～5% in the above-mentioned steps (1), and reaction time of esterification generally is 48～90 hours.
Above-mentioned steps (2) preferably uses butylacetate as solvent, and its consumption is 5～7 times of Mycophenolic Acid weight normally.
Above-mentioned steps (3) is better with the sodium hydrogen carbonate solution washing of 5%g/mL, detects the content of Mycophenolic Acid by TLC or HPLC and controls the washing terminal point.
Can add the feed intake anhydrous sodium sulfate drying of weight 3-5% of Mycophenolic Acid before above-mentioned steps (4) decolouring in organic phase, suction filtration then adds the 1-5% gac of Mycophenolic Acid weight, reflux decolouring 40min, insulation filtration again in filtrate.Later step (5) is concentrated into filtrate 3L concentrated solution/kg Mycophenolic Acid and feeds intake at 55 ℃～65 ℃, vacuum-0.08 ± 0.01MPa, slowly is cooled to 3～4 ℃, in 3～4 ℃ of crystallizations 12 hours.
Above-mentioned steps (6) obtains crystal with suction filtration or centrifugation method separation, at 40 ℃～60 ℃ drying under reduced pressure.For further improving the quality of products, the resulting product of step (6) can add dehydrated alcohol and discoloring agent reflux again, carries out secondary decolourization, after insulation is filtered, is concentrated, and the cooling recrystallization, the crystal drying is the mycophenolate mofetile powder of white.
The present invention is by discovering, Mycophenolic Acid and morpholine ethanol carry out esterification in organic solvents such as toluene product is purple, and its reason is that mycophenolate mofetile is easily oxidized and causes the product color burn.The present invention does not use solvent refluxing in esterification, and with Mycophenolic Acid and morpholine ethanol high temperature (120～150 ℃) esterification under the condition that antioxidant vitamin C exists, its product is the white solid powder, discoloring agent in follow-up purge process (gac) consumption has only 1～5% of Mycophenolic Acid charging capacity, just can solve color problem.
The preparation method of mycophenolate mofetile provided by the invention is a new synthetic process with industrial value, mainly has following advantage and positively effect:
At first; when the esterification of synthetic mycophenolate mofetile, do not use organic solvents such as benzene, toluene, but suitably increase the consumption of morpholine ethanol, avoided organic solvents such as toluene to leak the danger that causes accidentally; strengthened labour protection, increased the security of production process the workman.
Second, in esterification process, added vitamins C as antioxidant, effectively prevented the product color burn that causes because of oxidizing reaction in the esterification process, under the prerequisite that keeps the synthesizing efficient rate, solved a color burn difficult problem, significantly reduce the usage quantity of discoloring agent in the subsequent processes, reduced production cost, improved quality product; Simultaneously, compare with other antioxidant, vitamins C good water solubility, safety non-toxic, and in follow-up treating process, remove easily.
The 3rd, if use butylacetate to come lysate, compare after the esterification with normally used solvent ethyl acetate, the one, the boiling point of butylacetate is higher relatively, and the security of production process will be got well, and two are to use butylacetate yield when extraction higher.
Specific implementation method
Further describe the present invention below by embodiment, but the scope that does not limit the present invention in any way.
Mycophenolic Acid is joined in the morpholine ethanol of 3～7 times of weight, add the feed intake vitamins C of weight 1%～5% of Mycophenolic Acid simultaneously, carry out esterification 48～90 hours at 120 ℃～150 ℃, cool to room temperature, add the butylacetate of 5～7 times of Mycophenolic Acid weight; The sodium hydrogen carbonate solution washing that adds 5%g/mL, serves as the washing terminal point with HPLC analysis and Control Mycophenolic Acid content less than 0.2%g/mL, divide water-yielding stratum, add the feed intake anhydrous sodium sulfate drying of weight 3-5% of Mycophenolic Acid in mutually at organic solvent, suction filtration, filtrate adds the 1-5% gac of Mycophenolic Acid weight again, reflux decolouring 40min, insulation is filtered, filtrate is concentrated into 3L concentrated solution/kg Mycophenolic Acid and feeds intake at 55 ℃～65 ℃, vacuum-0.08 ± 0.01MPa, slowly be cooled to 3～4 ℃, in 3～4 ℃ of insulation crystallizations 12 hours.
The thick product of suction filtration or centrifugation was dry 5 hours of 40 ℃～60 ℃, vacuum-0.08 ± 0.01MPa.
Secondary decolourization: the amount by every kg crude product 7L adds dehydrated alcohol, and the gac reflux decolour 40min of adding crude product weight 1-5%, and insulation is filtered, dry, washing, concentrated.
Recrystallization: 50 ℃/-0.09MPa is concentrated into the 4L/kg crude product with the secondary decolourization filtrate decompression, slowly is cooled to 3～4 ° of C, in 3～4 ℃ of crystallizations 12 hours.
The brilliant separating, washing of tide: suction filtration or centrifugation tide are brilliant, wash by the amount of 4 ℃ of dehydrated alcohols of every kg brilliant 0.5L of tide.Continue centrifugal or suction filtration to doing.
Product drying: 50 ℃/-0.09MPa vacuum-drying obtained the mycophenolate mofetile product in 5 hours.
The mycophenolate mofetile product that obtains through aforesaid method is carried out mass analysis, and the leading indicator of this product is: content is greater than 99.5%; The HPLC chromatographic purity is greater than 99.7%; Single unknown impuritie is less than 0.1%; According to the mycophenolate mofetile quality standard that European Pharmacopoeia EP5.2 records,, colourless with clarification behind 96% dissolve with ethanol with reference to its appendix 2.2.2 method II.Quality product meets European Pharmacopoeia current standards.
The comparative example
The method that adopts U.S. Pat P5247083 to provide compares experiment, and its technology is specific as follows:
Do the inertia organic solvent with 50: 50 toluene and xylene mixture, with Mycophenolic Acid (40g, 0.125moles) join in the solvent that 40ml is made up of the mixture of toluene and dimethylbenzene and be heated to dissolving fully gradually, (19.65g is 0.15moles) with the 40ml solvent to add morpholine ethanol then.Stirred reaction mixture half an hour, under agitation be heated to 125 ℃ initial jar temperature (in backflow, raising 4 ℃ to 129 ℃) backflow 63h then.Detect fully at the HPLC of 63h and to show: 1) unreacted Mycophenolic Acid 4.79%; 2) impurity 0.35%, i.e. reaction finishes 94.9%.Solution colour is brown.Cooling vessel and solution add 2.8 gram acid-washed carbon.Heating container to 90 ℃ and keep 1h is used product the diatomite depth filtration, deep bed filtration afterwards then.Filtrate is separated to produce until no longer including distillment, container is cooled to 50 ℃ adds the 230ml ethyl acetate, and solution is moved into separating funnel, uses the 68ml water washing, washes 4 times with the 68ml saturated sodium carbonate solution then.Use the 68ml water washing at last.Distill ethyl acetate, product and 2.1g silica gel are handled 1h down at 50 ℃.90 milliliters of filtration, isolated ethyl acetate total amounts.With container protect heat 65 ℃ 1 hour to dissolve all products, cool to 42 ℃ and remain on this temperature 2.5h then, be cooled to-5 ℃ and remain on this temperature 8h at last.Filtration product, with cold ethyl acetate and SBP with 65/70 (1: 2v/v) mixture 45ml wash-out.60 ℃ of dry 3h under vacuum are lower than 1% until weight loss with product.Ultimate yield is 82.9%.
According to this technology the leading indicator of synthetic mycophenolate mofetile mass analysis: content is greater than 99%; The HPLC chromatographic purity is less than 99.5%; The mycophenolate mofetile quality standard of recording according to European Pharmacopoeia EP5.2 is with reference to its appendix 2.2.2 method II, with showing faint yellow or lavender behind 96% dissolve with ethanol.Do not meet the European Pharmacopoeia quality standard, need to make with extra care repeatedly just can reach this standard.
Claims (10)
1. the preparation method of a mycophenolate mofetile may further comprise the steps:
(1) Mycophenolic Acid and morpholine ethanol are mixed by weight 1: 3～7, and the adding vitamins C carries out esterification at 120 ℃～150 ℃;
(2) cool to room temperature, with butylacetate or ethyl acetate or the dissolving of its mixture;
(3) with the sodium hydrogen carbonate solution washing, collect organic phase;
(4) organic phase is decoloured with discoloring agent;
(5) concentrating under reduced pressure, decrease temperature crystalline;
(6) isolation of crystalline is carried out drying.
2. as the preparation method of claims 1 described mycophenolate mofetile, it is characterized in that ascorbic consumption is a Mycophenolic Acid weight 1%～5% in the described step (1).
3. as the preparation method of claims 1 described mycophenolate mofetile, it is characterized in that the time of described step (1) esterification is 48～90 hours.
4. as the preparation method of claims 1 described mycophenolate mofetile, it is characterized in that described step (2) uses butylacetate as solvent, its consumption is 5～7 times of Mycophenolic Acid weight.
5. as the preparation method of claims 1 described mycophenolate mofetile, it is characterized in that described step (3) detects the content of Mycophenolic Acid and controls the washing terminal point with the sodium hydrogen carbonate solution washing of 5%g/mL by TLC or HPLC.
6. as the preparation method of claims 1 described mycophenolate mofetile, it is characterized in that, in organic phase, add the feed intake anhydrous sodium sulphate of weight 3-5% of Mycophenolic Acid before described step (4) decolouring and carry out drying.
7. as the preparation method of claims 1 described mycophenolate mofetile, it is characterized in that the discoloring agent described in the step (4) is a gac, consumption is the feed intake 1-5% of weight of Mycophenolic Acid, the reflux decolouring.
8. as the preparation method of claims 1 described mycophenolate mofetile, it is characterized in that, described step (5) is the organic solution after the decolouring to be concentrated into 3L concentrated solution/kg Mycophenolic Acid at 55 ℃～65 ℃ feed intake, and slowly is cooled to 3～4 ℃ then, in 3～4 ℃ of crystallizations.
9. as the preparation method of claims 1 described mycophenolate mofetile, it is characterized in that described step (6) obtains crystal with suction filtration or centrifugation method separation, at 40 ℃～60 ℃ drying under reduced pressure.
10. as the preparation method of claims 1 described mycophenolate mofetile, it is characterized in that the product that step (6) obtains adds dehydrated alcohol and discoloring agent reflux again, carries out secondary decolourization, after insulation is filtered, is concentrated, the cooling recrystallization.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351821A (en) * | 2011-10-24 | 2012-02-15 | 福建和泉生物科技有限公司 | Method for separating mycophenolic acid fermentation liquid by ceramic film separation technology |
| CN102924413A (en) * | 2012-10-23 | 2013-02-13 | 福建科瑞药业有限公司 | Method for purifying and decolorizing mycophenolate mofetil |
| CN106866595A (en) * | 2017-03-04 | 2017-06-20 | 丽珠集团新北江制药股份有限公司 | A kind of MMF preparation method |
| CN113549040A (en) * | 2020-04-23 | 2021-10-26 | 鲁南制药集团股份有限公司 | Preparation method of mycophenolate mofetil impurity D |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4753935A (en) * | 1987-01-30 | 1988-06-28 | Syntex (U.S.A.) Inc. | Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions |
| US5247083A (en) * | 1992-07-10 | 1993-09-21 | Syntex (U.S.A.) Inc. | Direct esterification of mycophenolic acid |
| IN188985B (en) * | 1998-12-09 | 2002-11-30 | Biocon Ltd | |
| CZ292123B6 (en) * | 2001-06-08 | 2003-08-13 | Ivax Pharmaceuticals S.R.O. | Process for preparing mofetil mycophenolate |
| CN1328272C (en) * | 2005-08-22 | 2007-07-25 | 鲁南制药集团股份有限公司 | Industrial production method of mycophenolic acid morpholine ester |
| CN100402516C (en) * | 2005-10-18 | 2008-07-16 | 深圳市东阳光实业发展有限公司 | Prepn process of mofe-til mycophenolate |
-
2007
- 2007-03-16 CN CNB2007100865976A patent/CN100484930C/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351821A (en) * | 2011-10-24 | 2012-02-15 | 福建和泉生物科技有限公司 | Method for separating mycophenolic acid fermentation liquid by ceramic film separation technology |
| CN102924413A (en) * | 2012-10-23 | 2013-02-13 | 福建科瑞药业有限公司 | Method for purifying and decolorizing mycophenolate mofetil |
| CN102924413B (en) * | 2012-10-23 | 2014-12-31 | 福建科瑞药业有限公司 | Method for purifying and decolorizing mycophenolate mofetil |
| CN106866595A (en) * | 2017-03-04 | 2017-06-20 | 丽珠集团新北江制药股份有限公司 | A kind of MMF preparation method |
| CN113549040A (en) * | 2020-04-23 | 2021-10-26 | 鲁南制药集团股份有限公司 | Preparation method of mycophenolate mofetil impurity D |
| CN113549040B (en) * | 2020-04-23 | 2024-08-06 | 鲁南制药集团股份有限公司 | Preparation method of mycophenolate mofetil impurity D |
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| CN100484930C (en) | 2009-05-06 |
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Address after: 400000 No. 22, creative road, Beibei District, Chongqing Patentee after: CHONGQING DAXIN PHARMACEUTICAL Co.,Ltd. Address before: 400000 No. 22, creative road, Beibei District, Chongqing Patentee before: Peking University International Hospital Group Chongqing Daxin Pharmaceutical Co.,Ltd. Address after: 400000 No. 22, creative road, Beibei District, Chongqing Patentee after: Peking University International Hospital Group Chongqing Daxin Pharmaceutical Co.,Ltd. Address before: 400000 No. 22, creative road, Beibei District, Chongqing Patentee before: CHONGQING DAXIN PHARMACEUTICAL Co.,Ltd. |